Process for the preparation of debrominated analogues of bromo-steroids of the pregnane,androstane and cholestane series



US. Cl. 260-23955 18 Claims 9 ABSTRACT OF THE DISCLOSURE A process forthe preparation of a debrominated analogue of a bromo-steroid withoutattack on a normally readily eliminatable substituent carried by acarbon atom adjacent to the carbon atom carrying the bromo-substituentby reacting the bromo-steroid with a salt of a polyvalent metal in whichthe metal is in a lower state of valence capable of oxidation to ahigher state in the presence of a substance capable of providinghydrogen free radicals.

This application is a continuation-in-part of my copending applicationS.N. 418,903 filed on Dec. 17, 1964 and now abandoned.

This invention concerns a novel process for the reductive dehalogenationof organic halides, especially halogen-substituted steroids.

In the chemical synthesis of organic compounds it is frequentlynecessary to remove halogen from an organic halide without unwantedattack at other points in the molecule. Thus, for example, in previousattempts to dehalogenate halohydrins reductively, it has been found thatthe hydroxyl group was eliminated to give an unsaturated product. Thisproblem is especially frequent in the synthesis of complex carbocyclicstructures such as the steroids and alkaloids where there are commonly anumber of other groupings such as keto, acetyloxy, hydroxy, alkoxy,carboxy, etc. groups present and it is undesirable that these should beattacked. We have now found that organic chlorides, bromides, andiodides wherein the halogen atom is attached to a primary, secondary ortertiary carbon atom can readily be converted into their dechlorinated,debrominated or deiodinated analogues by reduction with a low-valencymetal ion or dissolving metal reducing agent in the presence of atransfer donor of hydrogen radicals. Our new process in general givescomparatively good yields and the selectivity is good.

By the term low valency metal ion reducing agent as used herein is meantreducing agents or systems supplying metal ions in a low valency statewhich are capable of ready oxidation to a higher valency state and henceexhibit reducing properties. Such reducing agents, include, for example,ferrous, titanous, thallous, stannous, chromous salts, etc. By the termdissolving metal reducing agents is meant reducing systems comprising ametal and a liquid which dissolves the metal to form a compound thereofthereby increasing the valency of the metal and leading to reduction ofother substances present. Such reducing systems include, for example,Zinc and acid, zinc amalgam or aluminum amalgam and water etc.

According to the present invention therefore we pro- United StatesPatent ice vide a process for the production of dechlorinated,debrominated or 'deiodinated analogues or organic halides wherein anorganic halide having one or more chlorine, bromine or iodine atomsattached to a primary, secondary or tertiary carbon atom is reacted witha substance selected from the group consisting of dissolving metals andlow-valency metal salts as reducing agent in the presence of a transferdonor of hydrogen radicals to replace said chlorine, bromine or iodineatom by a hydrogen atom.

The reducing agent is preferably a chromous salt of an organiccarboxylic acid, preferably of a lower (C alkanoic acid such as butyric,propionic or, preferably, acetic acid which may however, carrysubstituents e.g. halogen atoms. Chromous acetate is especiallysuitable. Other reducing agents of this type include other chromoussalts, titanous salts, thallous salts, zinc in acid etc.

It should be noted that while chlorine, bromine and iodine atoms may bereplaced by hydrogen in the process of the invention, fluorine atomsnormally remain unaffected.

The reaction is of particular interest in the field of steroid synthesisand has proved especially useful in the dehalogenation of chloro-, bromoand iodo-steroids carrying a monovalent oxygen function on a carbon atomadjacent to that adjacent to the carbon to which the halogen to beremoved is attached. The reaction normally proceeds readily withelimination of the adjacent oxygen function and similarly, an adjacentfluorine atom is also normally eliminated. The acyloxy group may, forexample, be a lower aliphatic acyl group, eg having 16 carbon atoms.Using the method according to the invention, 9a-bromo-11fi-hydroxysteroids, 9a-bromo-11B- fluoro steroids, l6fi-bromo-l7a-hydroxysteroids, 50:- brorno-6fi-hydroxy steroids and 5a-bromo-6fi-fluorosteroids have all been reduced on to produce their cle-brominatedanalogues.

By the term steroids? We mean compounds having the basiccyclopentanoperhydrophenanthrene ring structure and which maycontainvarious substituents and/or double bonds e.g. a keto, hydroxy oracyloxy group in the 3- position, alkyl groups in the 2-, 6- and16-positions, keto, or acetyloxy groups at the ZO-position, a keto,acyloxy, hydroxy or hydrocarbon group at the 17-position, a hydroxygroup, an acyloxy group or a fluorine atom at the 11- or 6-position, ahydroxy group at the l2-position, a double bond in the l and/ or4-position and/or a fluorine atom in the 11- or 6-position.

One especially interesting class of steroids which may advantageously besubjected to the process of the invention are the 11B-hydroxy-A-3-keto-steroids having a chlorine, bromine or iodine atom in the9a-positio'n. A -3-ketosteroids having an oxygen function at thell-position are common among the physiologically active steroids, forexample, cortisone, hydrocortisone, prednisone, prednisolone, 16-methylprednisolone, Il s-hydroxy progesterone, etc. In the synthesis of thesecompounds, it is commonly economically advantageous to start from morereadily available steroids which are unsubstituted at the ll-positionand to introduce subsequently the desired oxygen function. Many of themethods previously proposed for the introduction of an ll-oxygenfunction into the steroid molecule have been particularly elaborate'andrequired a large number of stages.

It has been found to be difficult to use reactions which take placeselectively at the ll-position and other functions in the molecule haveusually had to be protected previously and the protecting groups removedsubsequently. In particular, it has previously been found difficult tointroduce an ll-hydroxy substituent in the fl-configuration and methodsfor converting the more readily available lla-hydroxy steroids have alsobeen cumbersome.

The process of the invention enables the 9a-chloro-, bromoandiodo-llB-hydroxy-M-3-keto-steroids to be readily converted to theiranalogues possessing hydrogen at the Qa-POSitlOn without substantialelimination of the 11 fi-hydroxyl group.

The process of the invention also allows 6/3-hydroxy steroidsunsubstituted at the Sat-position to be prepared from the readilyavailable a,6,8-halohydrins. Such 6/3-hydroxy compounds are of use, forexample, as intermediates in the production of 19-nor or19-hydroxy-steroids.

The dehalogenation of the above 9ot-halogeuo-11B-hydroxy steriods isfound to tend to yield other compounds to a relatively small extent.Thus, for example, besides the desired product, the corresponding9(ll)-dehydrosteroid is formed by elimination of both halogen andhydroxyl as well as a further llfi-hydroxy compound which is a 5,9-cyclocompound. These products may be represented by the partial structures9(11)-dehydro-A B-keto-steroid keto-steroid It is found that dilferentreaction conditions tend to yield different proportions of theseproducts and it is not difiicult to select conditions which favor theproduction of the desired product at the expense of the other twosubstances.

The reaction according to the invention is also especially useful inallowing the preparation of 11,8-fluoro and 6fl-fluoro compounds havinghydrogen at the 90c and positions. :Such steroids are new compounds andin general possess enhanced biological activity as compared to theirnon-fluoro analogues. According to a further feature of the invention,therefore, we provide 9aunsubstituted llfi-fiuoro-steroids andSet-unsubstituted 6,6- fluoro steroids.

As indicated above, the hydrogen atom replacing the chlorine, bromine oriodine atom will be furnished by a substance present in the reactionmixture which provides hydrogen free radicals. Whilst it is not wishedto be bound by theoretical considerations, it is thought that thereaction proceeds by a preliminary transfer in which the halogen iseliminated, the reducing metal or metal ion being increased in valencyto supply the necessary electron, and a free radical being generated atthe position originally occupied by the eliminated halogen atom.Hydrogen is then supplied by hydrogen atom transfer from an appropriatesubstance present in the reaction mixture. Such substances include, forexample, H PO hydrides, such as triarylsilanes or triaryltinhydrides,1,4-dihydroaromatic compounds such as 1,4-dihydrobenzene and 1-benzyl-1,4-dihydronicotinamide, and related dienes such ascyclopentadiene, etc., and in particular, thiols. Thiols, which can berepresented by the general formula R.SH, undergo hydrogen atom transferespecially readily and we have found that in the reductivedehalogenation reaction of the invention, thiols greatly increase theyield of the desired dehalogenated analogues being themselves largelyconverted to disulphides RSSR. This last finding is suggestive of thefree radical mechanism which is postulated, since the conversion of R.SHto disulphide normally requires oxidising conditions.

The group R in the thiol may, for example, be an aliphatic, araliphaticor aromatic group which may if desired carry substituents such ashydroxy, ether, thioether, keto, carboxyl, esterified carboxyl groupsetc. Unsubstituted hydrocarbon groups are, however, preferred,

for example lower alkyl groups or unsubstituted aryl groups such asphenyl groups.

In the steroid series the starting compound may carry substituents at,for example, the 3, 6, 11, 16, 17 positions etc. or may be unsaturated,for example at C 1(2) or 4(5). Substituents which may be presentinclude, for example, hydroxy, keto, methylene-dioxy, acyl, alkyl,alkynyl groups etc. and fluorine atoms and in particular the groupingsat C 17 may be one of the groupings giving physiological activity, forexample keto, acetyl, 3- acetyl-a-hydroxy, etc. Reactive groups such asketo groups can, if desired, be protected e.g. by conversion toketal-groups. The 6 and/or 16 positions can advantageously carry alkylgroups, such as methyl groups, in the ocor ii-configuration. The halogenatoms to be removed may, for example, be in the 9a, 5ocor 16fi-p0sition.

The reducing agent is preferably present in at least stoichiometricquantities with respect to the steroid and is advantageously in excess.1 to 10 mols of reducing agent may, for example, be used, preferablyabout 5 mols.

The reaction is advantageously carried out in an inert solvent and thisis preferably polar. The principal consideration in choosing a solventis the solubility of the steroid starting compound. Thus, for example,the solvent may be an alcohol, ketone, cyclic ether or substituted amideor sulphone solvent, for example, methanol, ethanol, acetone, methylethyl ketone, dioxan, tetrahydrofuran, dimethylformamide (DMF),dimethylacetamide (DMA), dimethylsulphoxide (DMS) etc. Aprotic solventssuch as DMA, DMF and DMS are preferred.

The reaction temperature does not appear to be critical and may liebetween the freezing and boiling points of the reaction medium e.g.between about -50 and C. Conveniently, however, the reaction temperatureis about ambient.

Where the reducing agent is a chromous salt of a carboxylic acid, thismay conveniently be prepared by reacting chromous chloride with a saltof such an acid e.g. an alkali metal acetate, preferably in an inertatmosphere to avoid oxidation and preferably in water or ethanol assolvent. The chromous salt of the organic acid is normally precipitatedand may then be separated from the reaction mixture and, preferably,dried. Chromous chloride is conveniently prepared by reduction ofchromic chloride with amalgamated zinc dust.

In order that the invention may be well understood, the followingexamples are given by way of illustration only:

M.P.s taken on a Kofler-type hot stage, are uncorrected. Unless statedotherwise, ultraviolet spectra were determined in methanol and opticalrotation in chloroform. Infrared spectra were determined using anInfracord model 137 spectrophotometer.

EXAMPLE I Chromous chloride Amalgamated zinc dust was prepared by mixingtogether zinc dust (30 g.), mercuric chloride 1.2 g.), water (30 ml.),and concentrated hydrochloric acid (6 ml.) for 10 minutes and decantingthe supernatant liquid. A solution of chromic chloride hexahydrate (25g.) is freshly-boiled, deionized water (100 ml.) and concentratedhydrochloric acid (6' ml.) was added with swirling to the aboveamalgamated zinc dust in an atmosphere of carbon dioxide. Reduction(which takes about 2.5 'lours) was allowed to continue in this inertatmosphere.

Chromous acetate The bright-blue-coloured solution of chromous chloridewas added (care should be taken to avoid access to air at this stage)with swirling to a solution of sodium acetate crystals (50 g.) indeaerated and deionized water (100 ml.) kept under carbon dioxide,whereupon red chromous acetate precipitated rapidly. For filtration, the

following apparatus was found to be very convenient: The slurry ofchromous acetate was quickly transferred to a sintered glass filterwhich was provided with an airtight rubber stopper. The stopper wasfitted with carbon dioxide inlet and outlet tubes and a dropping funnel.During the transfer, filtration, washing, and dryingof the chromousacetate, dry carbon dioxide was passed through the filter. By carefulregulation of the carbon dioxide rate, a slight suction may be appliedto filter. The product was washed several times with small portions ofdeaerated and deionized water until the washings were free of chlorideions, as tested with silver nitrate solution. Drying was carried out bywashing it with a little absolute ethanol (preferably distilled in anitrogen atmosphere) and then with ether, the last traces of ether beingremoved be the stream of dry carbon dioxide (3 hours).

The brick-red chromous acetate powder must be completely dry in order toproduce a reasonably stable product before exposure to air, as it isoxidized very rapidly when wet. The purity (determined titrimetrically)of the freshly-prepared material varies from 75 to 85 percent. The yieldwas 12 g. or 75.5 percent of the theoretical based on chromic chloridehexahydrate. Its strength deteriorates in a few days even when kept in adesiccator previously filled with carbon dioxide.

9a-bromo-11fl-hydroxy steroids in dimethylsulphoxide were debrominatedon treatment with chromous acetate and n-butanethiol. The yield of thedebromo compound varies from 75 to 80 percent. A typical experiment isdescribed beloW.

Reductive dehalogenation of 9a-bromo-11fi-hydroxyprogesterone To astirred solution of 9a-bromo-1lfi-hydroxy-progesterone (0.5 gm),n-butanethiol (1 ml., ca. 7.5 mole equivalents) in dimethyl sulphoxide(40 ml. Matheson, Coleman and Bell; not further purified) was addedchromous acetate (1.35 g., 74% mole equivalents) at room temperature andin an atmosphere of carbon dioxide. Stirring was continued overnight.Carbon dioxide was allowed to pass for ca. 10 hours. The reactionmixture was then poured into ice water and extracted with methylenechloride. The extract was washed with water and dried over anhydroussodium sulphate. Evaporation of the solvent in vacuo gave crudecrystalline llfl-hydroxyprogesterone, which on treatment with ethylacetate (small volume) gave prisms (0.3 g., 75%), M.P. 182- l85 (lit.M.P. 186188). Chromatography of the concentrated mother liquor onacid-washed alumina (3.5 g.)

and elution with methylene chloride containing 0.4%

methanol yielded a further amount of the compound (24 mg.), M.P.165-180". The total yield was 0.324 g. (80.4%

EXAMPLE 2 'Example 1 was repeated using various solvents The results areset out in Table I below:

THF (70 ml.) (anh.) THF (70 ml.) (anh.) Benzene (anh) 100 ml Benzene(anh.) 100 ml. 5 Dlllgls (not distilled) =40 1 No reaction. In a blankexperiment in which 11 B-hydroxy-progester one Was treated underidentical conditions, the recovery of starting material was about 85%.

EXAMPLE 3 Example 2 was repeated using thiophenol (10 moles) in place ofn-methyl mercaptan and DMS (940 ml.) as solvent.llfl-hydroxy-progesterone was obtained in 75% yield and diphenyldisulphide was also isolated (by chromatography).

The experiment was repeated using tetrahydrofuran as solvent, both inthe light and in the dark and the results are shown in Table II below:

Example 1 was repeated using various thiols as hydrogen donors and theresults are shown in Table III below:

TABLE III Yield (percent) h at 118- y roxy- DMS, proges- Expt ml.Mercaptan terone 1 40 n-Butylthiol (7.5 mole equiv.) 2 30 Ethanethiol (5mole equiv.) 67 3 40 Methanethiol (ca. 30 mole equiv.) 81

EXAMPLE 5 Example 1 was repeated using 9a-bromo-cortisol acetate and 7.5mole equivalents of n-butylthiol giving a yield of 77% of cortisol.

EXAMPLE 6 Example 5 was repeated using 9or-bromo-cortisol bismethylenedioxide, giving a yield of 80% of cortisol bismethylene dioxide.

EXAMPLE 7 Chromous acetate reduction of 9a-bromo-1lB-hydroxyprogesterone in DMS (dimethylsulphoxide) To a stirred solution of thebromohydrin (500 mg.) in DMS (40 ml.), containing thiophenol (1.3 g., 10mole equivs.) was added chromous acetate (80%: 1.3 g., 5 moleequivalents) at room temperaturein a carbon dioxide atmosphere. Stirringwas continued overnight. Carbon dioxide was allowed to pass for 9 hours.The reaction mixture was poured into water and extracted with methylenedichloride. The extract was shaken with dil. sodium hydroxide solution(10%, ml.) for 15 minutes, Washed with water and dried. Chromatographyof the product (ca. 1.4 g.) over alumina (35 g.) in methylene chloridecontaining increasing amounts of methanol gave (1) bisphenyl disulphide(1 g.) M.P. 5961 and (2) llfi-hydroxy progesterone. Recrystallized fromethyl acetate this formed prisms (300 mgs., 74%), M.P. 188",[ed +2l5.4(c. 0.76 in acetone), A 242 mp. (6 16,000),

vfif; 3500 (s), 1700 (s), 1655 (vs), 1625 (m) cmr identical with anauthentic specimen (mixed M.P., IR. spectrum), [M.P. 186188, [or] +217(acetone), k 242 mp. (log e=4.26)].

EXAMPLE 8.

17,20:20,21-bismethylenedioxy-cortisol 3600 (a), 1675 (vs), 1625 (m)om."

' identical with an authenthic specimen (mixed M.P., LR.

spectrum), [M.P. 217-222", [11], +26]. The mother liquor onconcentration and chromatography over alumina gave a further crop (69mg.) M.P, 215-230". The total yield was 387 mg. (81% EXAMPLE 9Cortisol-2 l-acetate 9tx-bromocortisol 21-acetate (602 mg.) in DMS (35ml.) containing n-butyl mercaptan (1 ml.) was treated as in the previousexamples with chromous acetate (74%;

1.4 g., ca., 5 mole equivs.). Recrystallization of the crude productfrom methanol afforded cortisol-21-acetate (387 mg, 77%), M.P. 205-210",+1577" (c. 0.66), A 241 my (5 16,000),

vfi; 3500 (s), 3400 (s), 1750 (s),

1725 (s), 1630 (vs), 1235 (s) cm.- identical with an authentic specimen(mixed M.P., I.R. spectrum), [M.P. 216-2185", [a] +156 (c. 0.36),

Chromatography of the concentrated mother liquor over alumina (elutingwith methylene dichloride containing 0.5% methanol) gave a second crop(6 mg.) M.P. 202- 205. The total yield was 393 mg. (78%).

EXAMPLE Debromination of 9a-bromoprednisolone 2l-acetate M33" 1605 (W),1240 (s) GEL-1.

The above compound (2 g.) in purified dioxane (200 ml.) containing 0.5 Naqueous perchloric acid ml.)

and water (10 ml.) was treated with N-bromoacetamide (1 g.). After anhour of stirring, it was treated with dilute aqueous sodium sulphitesolution and extracted thoroughly with methylene dichloride. The extractwas washed with dilute sodium bicarbonate solution, water, dried andevaporated in vacuo. Recrystallization from acetone gave the9,11-bromohydrin as prisms (1.6 g.), M.P.183-189" dec., [11],; +142" (c.1.06 in dioxane), A 242 m (5 13,830).

W 3510 (m), 3400 (m), 1740 (m), 1720 (s), 1665 (vs),

max

1620 (In), 1605 (W).

(b) Prednisolone 21-acetate The above bromohydrin (600 mg.) in DMS ml.)containing l-butyl mercaptan (1 ml., ca. 7.5 mole equivs.) was treatedwith chromous acetate (74%, 1.4

g. ca., 5 mole equivs.) according to the general procedure.Recrystallisation of the product from methylene dichloridehexane gaveprednisolone ZI-acetate (350 mg.), M.P. 210-220", [57],; +111" (c. 0.72in dioxane), X 242 mu (6 14,550),

3500 (m), 1750 S 1725 (s), 1660 (vs), 1620 (s),

nuiol max 3500 and 3400 (unresolved), 1755 (s), 1725 (s), 1650 (vs),1590 (vs) MIL-'1.

identical with an authentic specimen; [M.P. 237-239" dec., [M 116"(dioxane), A 242 mg (6 15,000)]. A second crop (20 mg.) M.P. 217-222"was obtained from the mother liquor. Net yield was 74%.

Similar reduction using methane thiol (3 ml., ca. 43 mole equivs.)afiorded prednisolone acetate (380 mg., 76%), M.P. 212-220, [a] =+111 (a0.66 in dioxane) EXAMPLE 11 Chromous acetate reduction of9a-bromo-11B-hydroxy progesterone in DMS containing (a) 1,4cyclohexadiene.The bromohydrin (500 mg.) in DMS (30 ml.) containing1,4-cyclohexadiene (2 g., ca. 20 mole equivs.) was treated with chromousacetate 1.4 g., ca. 5 mole equiv.) according to the general procedure.Chromatography of the reaction product over alumina (20 g.) and elutionwith methylene dichloride containing increasing proportions of methanol(0.40%) gave 11,8-hydroxy progesterone (268 mg., 66%), M.P. 180-185",identical with an authentic specimen (M.P. and LR. spectrum).

(b) Triphenylsilane.The bromohydrin (500 mg.) in DMS (35 ml.) containingtriphenylsilane (1.5 g., ca. 5 mole equivs.) was treated with chromousacetate (70%, 1.4 g.) as before. Chromatography of the crude product(ca. 1.7 g.) over alumina (40 g.) and elution with methylene dichloridecontaining increasing proportions of methanol gave the followingfractions:

(1) mostly triphenylsilane 1.14 g., M.P. 44-45,

nuinl 11 2140 (vs), 1590 (W), 1425 (vs), 1110 (vs) cmf (2) llfl-hydroxyprogesterone (163 mg, 40%), M.P.

(3) llfl-hydroxy 5,9-cyclo pregnane-3,20-dione (97 mg.,

(1) a mixture of hexaphenylditin and perhaps triphenyltin bromide (1.45g.) M.P. 95-215".

(2) A mixture of llfi-hydroxy progesterone and trace of organo tincompound (eluted with 0.5% methanol) ca. 300 mg.

The latter on rechromatography and crystallization from ethyl acetategave llfl-hydroxy progesterone (261 mg, 65%) M.P. 182-188".

EXAMPLE 12 3 B-acetoxy-6 B-hydroxy-androstanl 7-one A solution of 522mg. of 3fi-acetoxy-5a-bromo-6/ihydroxy-androstan-l7-one in DMS (35 ml.)and n-butyl mercaptan (1.5 ml., 11 mole equivs.) was treated withchromous acetate (73%, 1.4 g., 5 mole equivs.) according to the generalprocedure. Chromatography of the crude product over acid-washed alumina(20 g.) in methylene dichloride afforded the debromo steroid as prisms(277 mg, 65%), M.P. -182". For analysis it was recrystallized from ethylacetate: hexagonal prisms, M.P. 183-184", [11],; +409 (c. 1.07),

m 3600 (s), 3000 (s), 2900 (S), 17501725 (vs), 1240 (vs) emfAnalysis.--Calcd. for C H O C, 72.36; H. 72.36; H, 9.29; O, 18.37.Found: C, 72.72; H, 9.17; O, 18.33.

EXAMPLE 13 1lfl-fluoro-M-pregnene-17a,2l-diol-3,20-dione-2l-acetate9a-bromo 11/8 fluoro-A -pregnene-17a, 21 diol-3,20- dione-2l-acetate(600 mg.) in DMS (50 ml.) containing n-butyl mercaptan (2 ml., 14.8 moleequivs.) was treated with chromous acetate (70%, 1.4 g.) according tothe general method. After working up in the usual way, a crystallineresidue (ca. 500 mg.) M.P. 185-193 was obtained. This did not containany bromine (Beilstein). A thin-layer chromatogram (19:1 methylenedichloridemethanol mobile phase) showed essentially one component (R;0.57). Recrystallization from ethyl acetate gave prisms (474 mg, 94%),M.P. 196204. The analytical sample had M.P. 204206, [M +142.8 (c. 0.57),k 240 m (e 15,360),

3300 (broad), 1750 (s), 1725 (s), 1665 (s), 1620,

3510 (In), 1730 (m), 1705 (s),

1675 (s), 1620 (w) cm."

Its infra-red spectrum differed from that of the main product.

nu iol max.

EXAMPLE 14 (a) 9a-bromo pregna-1,4-dien-11 8-ol-3,20-dionePregna-1,4,9(11-)-triene-3,20-dione (24.5 g.) in purified dioxane (1,600ml.) containing 1 N aqueous perchloric acid (164 ml.) and water(3281111.) was treated with N- bromoacetamide (16.4 g.). After 3 hrs. ofstirring at room temperature, it was treated with dilute aqueous sodiumsulphite solution and extracted thoroughly with methylene r chloride.The extract was washed with dilute sodium bicarbonate solution, water,dried and evaporated in vacuo. Trituration of the crude residue withethyl acetate gave the required bromohydrin as prisms, (25 g., 78.5%),M.P. 164-167 (dec.), t

3500 (m, br), 1710 (s),v 1665 (vs),

1625, 1615 (s, unsplit) cm. The analysis indicated the content of thecorresponding 9(11) olefin to be less than On recrystallisation frommethanol this had M.P. 177-178 (dec.). 1

Analysis.Calcd. for C H O Br: C, 61.80;. H, 6.68; 1?

0, 11.79; Br,19.62. Found: 0, 61.71;-H, 6.94; 0, 11.90; Br.19. s2. 1

(b) Pregna-1,4-dien-1113-ol-3,20-dione' The bromohydrin from (a) (8.83.g.) in dimethylsulphoxide (340 ml., redisti-lled) containing l-butanethiol (18.5 ml., 7.9 mole equivalents) was treated with stirring withchromous acetate (12. g., 75% purity as determined by titration, about2.44 mole equivs.) under carbon dioxide atmosphere for 17hrs. (forconvenience). The re- 3650, 3500 (s, doublet), 1700 (s), 1665 (vs),

1620(s) and 1610 (w, sh) cm.

The filtrate was concentrated and chromatographed on acid-washed aluminag.). Elution with methylene chloride containing increasing amounts ofmethanol gave (i) crude dibutyl disulphide ca. 2.4 g., which ondistillation furnished an oil (2.05 g.), B.P. 135/ca. 22 m., n 1.4882(identical with an authentic specimen, 11 1.4905 by T.L.C. and I.R.).

(ii) The desired debromosteroid (1.87 g.) M.P. 230- 233". Total yieldwas 5.69 g. (80%). This was identical with a specimen obtained bydehydrogenation of lip-hydroxyprogesterone. The analytical specimen(methanol) had M.P. 242-243.

Analysis.Calcd. for C H O C, 76.79; H, 8.59; O, 14.62. Found: C, 76.72;H, 8.57; O, 14.83.

EXAMPLE 15 1lB-fluoropregna-1,4-diene-17a,2ldiol-3,20-dione-2lacetate bychromous acetate reduction A dimethyl sulphoxide solution (10 ml.) of9a-bromo- 11,8-fluoropregna-1,4-diene-17,21-diol-3,20-dione-21 acetate(200 mg.) was deoxygenated by stirring at room temperature for one hourunder a stream of carbon dioxide. n-Butylthiol (0.5 ml.) and chromousacetate (750 mg.) were added. The system was then stoppered and stirredovernight. After twenty hours the deep-red mixture was poured intotwenty volumes of water containing saturated aqueous sodium chloridesolution (20 ml.) whereupon the colour became green. (Simple exposure toair also causes the reaction mixture to become green). The aqueousmixture was extracted with methylene chloride which in turn was washedwith water (five times). Upon filtration and evaporation of solvent atreduced pressure, a residue (225 mg.) was obtained which showed only oneultraviolet light absorbing spot (Rf 0.5) when chromatographed on a thinlayer silica gel plate impregnated with fluorescein using 5% methanol inmethylene dichloride. Chromatography on acid-washed alumina (10 g.)provided a polar fraction (128 mg.) of unclean semi-solid material wheneluted with 0.5% methanol in methylene chloride. Recrystallisation fromacetone/cycllohexane gave 53 mg. (32%) of clean crystals (M.P. 195-206")which gave a negative Beilstein reaction. On combining with identicalmaterial from several other runs and recrystallizing fromacetone/cyclohexane to constant melting point (206- 209"), a pure samplewas obtained for analysis.

A nalysis.C-alculated for C H O F: C, 68.32; H, 7.18; F, 4.70. Found: C,68.40; H, 7.42; F, 4.07.

The analytical physical constants were M.P. 206-209 [a] =-l-103, A (KBr)1610, 1630, 1660, 1710, 1740 cmf A (MeOH)=24l I'D/.1. (14.500).

EXAMPLE 16 Treatment of 9a-bromo-1lp-hydroxyprogesterone with chromousacetate and hypophosphorous acid in dimethylsulphoxide Adimethylsulphoxide solution 10 ml.) of bromohydrin (285 mg.) andhypophosphorous acid (0.5 ml. 50% aqueous) was deoxygenated by stirringunder a stream of carbon dioxide for one hour. Addition of chromousacetate (0.80 g.) caused an immediate green coloration throughout.Within an hour the reaction mixture'had become purple. The flask wasstoppered and stirring was continued overnight. The contents were pouredinto water (250 ml.)

containing saturated sodium chloride solution (25 ml.), which was thenextracted with methylene chloride. The methylene chloride was washedwith'water (five times), filtered and evaporated. The residue ontreatment with ethyl acetate provided crystalline material (200 mg.,87%,

M.P. -187 which had an infrared. spectrum (KBr) identical tollfl-hydroxyprogesterone. Recrystallization from ethyl acetate gave apure sample (M.P. -189),

1 l the melting point of which was not depressed by admixture with theauthentic compound.

EXAMPLE 17 (a) Bromofluorination of l6a-methyl-pregna-1,4,9(l1)-triene-17a,21-diol-3,20-dione-2l-carbethoxylate Anhydrous hydrogenfluoride (33 g.) was distilled into a polyethylene flask (in a DryIce-acetone bath) containing tetrahydrofuran (50 ml., unpurified). Thetitle steroid (2.300 g., 5.3 mmol.) and N-bromoacetarnide (835 mg., 6.0mmol.) in separate tetrahydrofuran solutions were cautiously poured intothe reaction flask. The solution was stirred magnetically for one hourin the Dry Ice bath and for two hours in an ice water bath. It was thenslowly and carefully poured into an iced sodium carbonate solution (2litres, 10%) with stirring. The mixture was extracted with methylenechloride. The organic solution was washed with water, filtered andevaporated at reduced pressure. The residue was crystallized fromacetone/cyclohexane. The yield was 2.325 g. (83%), M.P. 195-199 dec.Recrystallization of a small portion to constant melting point (205-206dec.) provided a pure sample (solvated). It was heated to constantweight at 100 under vacuum. +104; A (KBr) 1610, 1625, 1665, 1730, 1750,3000, 3700 cm. A (MeOH) 240 m (13,000).

Analysis.-Calcd. for C H O BrF: C, 56.92; H, 6.07; Br, 15.19; F, 3.61.Found: C, 57.00; H, 5.99; Br, 14.88; F, 3.59.

(b) Reductive debromination of 9a-bromo-11fl-fluoro- 16a-methyl-pregna1,4 diene-17a,21-diol-3,20-dione- 21-carbethoxylate The title steroid(1.910 g.) was dissolved in dimethylsulphoxide (35 ml.) and the solutionwas deoxygenated by bubbling in a brisk stream of carbon dioxide whilestirring magnetically. After one hour, n-butylthiol (5.0 ml.) andchromous acetate (4.6 g.) were added. The carbon dioxide bubbler wasremoved and the flask was stoppered and stirred overnight. The purplesolution was poured into a dilute (0.1 saturated) aqueous sodiumchloride solution (500 ml.). The steroid was extracted with methylenechloride and washed well (five times) with water. The residue obtainedon evaporation of the organic solvent was chromatographed on acid washedalumina (50 g.). The eluants were benzene, methylene chloride, then 0.4%methanol (in methylene chloride). This last eluted 1.4 g. of steroid inthree fractions which appeared only slightly impure on examination bythin layer chromatography. Crystallization from methanol provided 750mg. (46%) of material, M.P. 178-181. The use of acetone/cyclohexane gaveless material and of inferior quality. It was recrystallized frommethanol to constant melting point 176-178. +80; r (MeOH) 242 m,(14,700); A (KBr) 1600, 1620, 1660, 1730, 1765, 3000, 3500 cm.

Analysis.-Calcd. for C H O F: C, 66.96; H, 7.37; F, 4.24. Found: C,66.76; H, 7.32; F, 3.97.

EXAMPLE 18 The use of I-benzyl-l,4-dihydrnicotinamide as hydrogen donorin standard reductive debromination A deoxygenated dimethylsulphoxidesolution ml.) of 9a-bromo-1lfi-hydroxyprogesterone (250 mg.) was treatedwith benzyl dihydronicotinamide (prepared according to D.Mauzerall andF. H. Westheimer, JACS 77, 2261 (1955)) (340 mg.) and chromous acetate(750 mg.), and was stirred overnight in an atmosphere of carbon dioxide.After standing for an additional twenty four hours it was poured into adilute (0.1 saturated) aqueous solution of sodium chloride (250 ml.).The organic material was extracted with methylene chloride which in turnwas washed with water, hydrochloric acid (1 N) and three more portionsof water. Solvents were stripped at reduced pressure. The residue (225mg.) on examination by T.L.C. showed a major and a minor component atthe proper polarity (R; 0.3 with 3% methanol in methylene chloride).Chromatography on acid washed alumina (11 g.) provided a polar fraction(165 mg. eluted by 0.5% methanol in methylene chloride) which wascrystallized from ethyl acetate to yield pure 1113-hydroxyprogesteronemg., 67%, M.P. 188-192"). The infrared spectrum (KBr) was identical toan authentic sample.

EXAMPLE 19 The reductive debromination of 5u-bromocholestan-3/3,6p-diol-3-acetate Dimethylsulphoxide (25 ml.) was deoxygenated bybubbling carbon dioxide for one hour. Chromous acetate (0.78 g.),n-butyl thiol (1.0 ml.), and the title steroid (275 mg.) were added. Theflask was stoppered and stirred for three days.

The usual workup was followed by chromatography on acid washed aluminaand recrystallization from cyclohexane to yield mg. (67%) of6fi-hydroxycholesterylacetate, M.P. 162-165, which had an infraredspectrum (KBr) identical to an authentic sample.

EXAMPLE 20 Reductive debromination of 9a-brorno-1lfi-hydroxypregn-4-en-3,20-dione ll-formate The title steroid (450 mg.),dimethylsulfoxide (25 cc.), 1,4-cyclohexadiene (2 cc.), and chromousacetate 1.0 g.) gave IIB-hydroxyprogesterone ll-formate, M.P. 155- 60,lit. 157-61". A sample of this material, after 3 hrs. of treatment withsodium hydroxide (1%) in refluxing methanol, gavellp-hydroxyprogesterone. In the absence of cyclohexadiene, the chiefproduct was A -dehydroprogesterone.

EXAMPLE 21 Reductive debromination of 9a-bromo-11,6-hydroxypregn-4-en-3,20-dione ll-trifluoracetate The title steroid (480 mg.),dimethylsulphoxide (25 cc.), 1,4-cyclohexadiene (2 cc.) and chromousacetate (1.0 g.) gave 11;3-hydroxy progesterone ll-trifluoracetate.

In the absence of cyclohexadiene, the product consisted almost entirelyof A -dehydroprogesterone.

EXAMPLE 22 Reductive debromination of 16fl-bromopreg-5-en-3fl,17-diol-20-one 3-acetate The title steroid (0.555 g.), dimethylsulfoxide(34 ml.), n-butanethiol (1 ml.), and chromous acetate (1.4 g.) gave acrude product (280 mg.), which on chromatography on acid-washed aluminaafforded 3B,17a-dihydroxy-preg 5 en-20-one 3-acetate (162 mg., 35%).

EXAMPLE 23 Reductive debromination of5a-bromo-3fl,6p-dihydroxyandrostan-17-one 3-acetate The title steroid(522 mg.), dimethylsulfoxide (35 ml.), n-butanethiol (1.5 ml.), andchromous acetate (1.4 g.), after chromatography on acid-washed alumina,gave 3,8, 6/3-dihydroxyandrostan-17-one 3-acetate (277 mg., 65% M.P.165-82 (analytical sample recrystallized from ethyl acetate had M.P.183-5", +40.9,

2. 3600 (s), 1750-1725 (vs), and 1240 (vs) cmf Analysis.-Calcd. for C HO C, 72.36; H, 9.29; O, 18.33. Found: C, 72.72; H, 9.17; O, 18.33.

I claim:

1. A process for the preparation of a debrominated analogue of abromo-steroid of the pr'egnane, androstane or cholestane series whichhas a fluorine atom or a readily eliminatable monovalent oxygen functionattached to a carbon atom adjacent to that to which the bromine atom isattached, comprising reacting said bromosteroid with a salt of apolyvalent metal in which the metal is in a lower state of valencecapable of oxidation to a higher state in the presence of a substancecapable of providing hydrogen free radicals, whereby said bromine atomis replaced by a hydrogen atom and attack on said su'bstituent on saidadjacent carbon atom is minimized.

2. A process as claimed in claim 1 in which said salt is a chromous saltof a lower carboxylic acid.

3. A process as claimed in claim 2 in which said acid is an alkanoicacid of from 1-6 carbon atoms.

4. A process as claimed in claim 1 in which said salt is chromousacetate.

5. A process as claimed in claim 1 in which said bromosteroid has abromine atom in one of the positions 5w, 90cand 165-.

6. A process as claimed in claim 1 in which the bromosteroid possesses ahydroxy group attached to a carbon atom adjacent to that to which thebromine atom is attached.

7. A process as claimed in claim 1 in which the bromosteroid possessesan acyloxy group attached to a carbon atom adjacent to that to which thebromine atom is attached.

8. A process as claimed in claim 7 in which said acyloxy group is aformyloxy group.

9. A process as claimed in claim 1 in which the bromosteroid is a9a-bromo-1l 8-fiuoro-steroid.

10. A process as claimed in claim 1 in which said bromo-steroid is anl1fi-hydroxy-A -3-keto-steroid having a bromine atom in the 9u-position.

11. A process as claimed in claim 1 in which said bromo-steroid is a6B-hydroxy steroid havlng a bromine atom in the Set-position.

12. A process as claimed in claim 1 in which said substance capable ofproviding hydrogen free radicals is a member selected from the groupconsisting of a triaryl silane, a triaryltinhydride, 1,4-dihydrobenzeneand l-benzyl-1,4-dihydronicotinamide.

13. A process as claimed in claim 1 in which said substance capable ofproviding hydrogen free radicals is a thiol.

14. A process as claimed in claim 13 in which said thiol is a memberselected from the group consisting of a lower alkyl thiol andthiophenol.

15. A process as claimed in claim 13 in which the thiol isn-butanethiol.

16. A process as claimed in claim 1 in which 1 to 10 mols of saidsubstance capable of providing hydrogen free radicals are used withrespect to said bromo-steroid.

17. A process as claimed in claim 1 in. which the reaction is effectedin an inert polar solvent.

18. A process as claimed in claim 17 in which said solvent is a memberselected from the group consisting of an alcohol, ketone, cyclic ether,substituted amide and sulphone.

No references cited.

HENRY A. FRENCH, Primary Examiner US. Cl. X.R.

